This invention relates to biologically active materials, and, in particular, to materials which comprise a polymer linked to a biologically active agent. The invention is concerned with materials known as polymer-drug conjugates which typically contain a therapeutic agent, in particular, an anti-cancer drug, linked to a polymer backbone. The linkage between the polymer and the drug is by covalent bonding.
In designing a polymer-drug conjugate, the aim is to deliver a drug effectively to a therapeutic site such as a tumour. It is known, for instance, that polymer-drugs given intravenously can accumulate selectively in solid tumour tissue by the EPR effect.
The most commonly used anticancer agents are low molecular weight compounds which readily gain access to cells by rapid passage across the cell membrane. After intravenous (IV) administration, a large percentage of the injected dose leaves the circulation within a few minutes, resulting in a ubiquitous body distribution of drug and little selective concentration in tumour tissue. By creating a macromolecular polymer-anticancer drug conjugate, there is provided an opportunity to improve tumour specific targeting, to minimise drug entry into sites of toxicity, to control precisely the rate of drug liberation at the target site (giving opportunities for long-term controlled release) and deliver the active principal intracellularly, providing a means to overcome p-glycoprotein related multidrug resistance.
Numerous polymers have been proposed for synthesis of polymer-drug conjugates including polyaminoacids, polysaccharides such as dextran, and synthetic polymers such as N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. However, these polymers have limitations. For example, a dextran-doxorubicin conjugate has been tested clinically and been found to be much more toxic than the parent drug and the HPMA copolymers which have been clinically tested have the disadvantage of being non-biodegradable in the main chain.
The present invention provides a polymer-drug conjugate in which the polymer is the polysaccharide dextrin. The polymer-drug conjugate may be one in which the polymer is linked directly to the drug or one in which the polymer is linked indirectly to the drug, for instance, by means of a xe2x80x9cbiodegradable spacerxe2x80x9d to which both the drug and the polymer are linked. The dextrin is preferably a non-cyclic dextrin.
It has been found that dextrin is not only a suitable material for forming a biocompatible polymer-drug conjugate capable of delivering a drug to a target site and of releasing the drug at such a site but is also biodegradable in a manner such that it may be used at a molecular weight which is suitable for the particular drug and its application without any upper limit imposed by the need to ensure excretion of the polymer.
The term xe2x80x9cdextrinxe2x80x9d means a glucose polymer which is produced by the hydrolysis of starch and which consists of glucose units linked together by means mainly of alpha-1,4 linkages. Typically dextrins are produced by the hydrolysis of starch obtained from various natural products such as wheat, rice, maize and tapioca. In addition to alpha-1,4 linkages, there may be a proportion of alpha-1,6 linkages in a particular dextrin, the amount depending on the starch starting material. Since the rate of biodegradability of alpha-1,6 linkages is typically less than that for alpha-1,4 linkages, for many applications it is preferred that the percentage of alpha-1,6 linkages is less than 10% and more preferably less than 5%.
Any dextrin is a mixture of polyglucose molecules of different chain lengths. As a result, no single number can adequately characterise the molecular weight of such a polymer. Accordingly various averages are used, the most common being the weight average molecular weight (Mw) and the number average molecular weight (Mn). Mw is particularly sensitive to changes in the high molecular weight content of a polymer whilst Mn is largely influenced by changes in the low molecular weight of the polymer.
It is preferred that the Mw of the dextrin is in the range from 1,000 to 200,000, more preferably from 2,000 to 55,000.
The term xe2x80x98degree of polymerisationxe2x80x99 (DP) can also be used in connection with polymer mixtures. For a single polymer molecule, DP means the number of polymer units. For a mixture of molecules of different DP""s, weight average DP and number average DP correspond to Mw and Mn. In addition DP can also be used to characterise a polymer by referring to the polymer mixture having a certain percentage of polymers of DP greater than a particular number or less than a particular number.
It is preferred that, in the dextrin-drug conjugate of the present invention, the dextrin contains more than 15% of polymers of DP greater than 12 and, more preferably, more than 50% of polymers of DP greater than 12.
The drug loading on the polymer is preferably from 0.5 to 99.5 mole %.
A targeting group may be attached either directly or indirectly to the polymer of the conjugate. It is preferred that the ratio of drug to targeting group is from 1:99 to 99:1.
Preferably the dextrin used in a dextrin-drug conjugate of the present invention is water soluble or at least forms a suspension in water.
The dextrin of a dextrin-drug conjugate of the invention may be in the form of either unsubstituted dextrin (as obtained by the hydrolysis of the starch) or may be substituted by one or more different groups. The substituents may be negatively charged groups, for instance, sulphate groups, neutral groups or positively charged groups, for instance, quaternary ammonium groups. In the case where the subsistent group is sulphate, it is preferred that the sulphated polysaccharide contains at least one sulphate group per saccharide (glucose) unit. A particular dextrin sulphate is dextrin-2-sulphate.
Examples of drugs which may form suitable conjugates with dextrin are:- alkylating agents such as cyclophosphamide, melphalan and carmusline; antimetabolites such as methotrexate, 5-fluorouracil, cytarabine and mercaptopurine; natural products such as anthracyclines (eg daunorubicin, doxorubicin and epirubicin), vinca alkaloids (eg vinblastine and vincristine) as well as dactinomycin, mitomycin C, taxol, L-asparaginase and G-CSF; and platinum analogues such as cisplatin and carboplatin.
The present invention also provides a pharmaceutical composition comprising a dextrin-drug conjugate and a pharmaceutically acceptable excipient or diluent therefor.
In addition, the present invention provides the use of a polymer-drug conjugate of the invention in the treatment of a medical condition in connection with which the drug is effective, Furthermore, the invention provides the use of a polymer-drug conjugate of the invention in the manufacture of a medicament for use in the treatment of a medical condition in connection with which the drug is effective.
The present invention also provides a method of treating an animal subject, including a human being, including treating the animal subject with a pharmaceutically effective dose of a dextrin-drug conjugate. The conjugate may be administered by any appropriate method, for instance, intravenously, intraperitoneally, orally, parentally or by topical application.
Various methods have been proposed for the preparation of polymer-drug conjugates. Within the scope of the present invention is a method comprising succinoylating dextrin and reacting the succinoylated dextrin with a drug or reactive derivative thereof.
Preferably, the dextrin is dissolved in anhydrous dimethyl formamide and is contacted with dimethyl amino pyridine and succinic anhydride. The resultant mixture is then purged with an inert gas and chemical reaction is allowed to take place over a prolonged period, preferably at least 12 hours.
The resultant succinoylated dextrin is reacted with a drug or drug derivative eg. doxorubicin hydrochloride to form the polymer-drug conjugate.